Influenza A viruses are responsible for the major pandemics of influenza in the last century and also the causative agents for most of the annual outbreaks of epidemic influenza. The WHO estimates that epidemic influenza affects approximately 5-15% of the global population annually, and is responsible for up to 3-5 million cases of severe disease and 500,000 deaths per year. WHO Influenza Fact sheet 211. World Health Organisation, Geneva, Switzerland (2003).
Influenza A virus is a member of the Orthomyxovirus family, and has a wide host range, including humans, horses, dogs, birds, and pigs. It is an enveloped, negative-sense RNA virus composed of a set of 8 RNA segments (abbreviated as PB2, PB1, PA, HA, NP, NA, M and NS) encoding at least 10 viral proteins. The HA segment encodes the hemagglutinin (HA) protein. The NA segment encodes the neuraminidase (NA). Based on serological classification, 16 HA subtypes (designated as H1 through H16) and 9 NA subtypes (designated as N1 through N9) have been thus far identified. Subtypes of influenza A that are currently circulating among people worldwide include H1N1, H1N2, and H3N2 viruses; H5N1 and H9N2 are circulating in birds such chickens; and H1N1 and H3N2 are circulating in pigs.
Current inactivated influenza vaccines are trivalent, containing 15±g HA of two influenza A (H1N1 and H3N2) subtypes and one influenza B strain. The basic technology and principles of vaccine production have remained much the same since their first introduction into clinical uses in the 1940s. The conventional wisdoms have focused on the optimization of production procedures to produce a conventional virus preparation with the maximum amount of HA proteins. In addition, influenza vaccines are standardized solely on the basis of HA content.
Vaccine efficacy declines as the antigenic relatedness between the circulating viruses and the viruses selected for the vaccine becomes more distant within the same subtype. Influenza virus undergoes two types of antigenic variation, “antigenic drift” and “antigenic shift”. Antigenic drift is part of the continuing occurrence of new influenza strains that differ from their ancestors by mutations in the HA and NA genes. The amount of change can be subtle or dramatic. The second type of antigenic variation is “antigenic shift”. A genetic shift can occur when two different influenza viruses, co-infecting the same host, exchange a whole genomic segment. This could result in a “reassortant” virus with a novel gene constellation and consequently with new properties. A genetic shift can also occur when a virus subtype crosses the species barrier directly without reassortment in an intermediate host. The antigenic variation of influenza viruses forms the primary basis for the occurrence of annual influenza epidemics and occasional pandemics and necessitates constant evolution of vaccine composition. For influenza vaccines, strain selection of the three viruses to be included in the annual seasonal vaccine now occurs twice a year at the WHO. While the selected strains are usually antigenically close to circulating strains, in some years they are not. Furthermore, avian H5N1 and swine H1N1 in recent years caused pandemic fears. Therefore, there is a need to have vaccines that will produce broadened protective immunity.